Retroviral infection is associated with pathological conditions in the human central nervous system. For example, HTLV-I infection is associated with HTLV-I associated myelopathy/tropical spastic paraparesis, a chronic neurodegenerative disorder. There have been reports of a similar disorder associated with HTLV-II. In addition, some patients infected with HIV-1 suffer from dementia associated with neuronal degeneration. The purpose of this project is to examine the ability of these viruses to infect cells of the human CNS, with particular emphasis on neurons, and to examine any alterations in the pattern of gene expression in those cells as a result of infection. In an effort to examine cells closely resembling primary human neurons, we have examining post-mitotic neuronal cells (NT2/N) derived from a teratocarcinoma cell line (NT2/D1). These cells display biochemical, morphological and functional characteristics of primary human neurons. Co-culture of NT2/N with HTLV-I or HTLV-II-infected cell lines results in the infection of NT2/N with the subsequent expression of HLA class I and class II genes. These results build on similar previous findings in a neuroblastoma model and suggest that neurons may have the potential to express HLA gene products and thereby be active participants in an immune response possibly contributing to the disease process. Additional studies have been examining the potential role of HTLV-I Tax in the development of neurological disease. It has been previously demonstrated that cells infected with HTLV-I secrete a soluble form of Tax, which has the ability to influence the expression of several cellular genes. Treatment of NT2/N cells with soluble HTLV-I Tax results in the induction of TNF-a gene expression as detected by RT-PCR and by ELISA. TNF-a is known to possess neurotoxic activity. Synthesis of TNF-a in response to soluble Tax occurs in a dose-responsive fashion between 2.5 nM and 25 nM and peaks within 6 hours of treatment. Untreated cells and cells treated with a mock bacterial extract produce no detectable TNF-a. Interestingly, treatment of the undifferentiated parental teratocarcinoma cell line, NT2/D1, with soluble Tax does not result in TNF-a synthesis, suggesting that differentiation-dependent, neuron-specific factors may be required. Extended treatment with soluble Tax results in morphological evidence of Tax-dependent marked cell death (within 3 days of treatment). A possible apoptotic mechanism to account for this apparent Tax-induced neuronal cell death is currently being investigated.